FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing a material comprising a
macrocyclic ligand and for producing a pharmaceutical liquid formulation of a complex
of said ligand with a lanthanide or a similar compound, which can be used as contrast
agents for magnetic resonance imaging.
BACKGROUND OF THE INVENTION
[0002] Magnetic resonance imaging (MRI) is a powerful, non-invasive technique used to produce
detailed two or three-dimensional anatomical images of tissues in the body. Conventional
MRI uses the proton
1H as its signal source which is highly abundant in tissues and it has the highest
sensitivity of all the biologically relevant nuclei.
[0003] The contrast, which makes the differentiation of internal structures possible in
the image, arises from how the signal decays and is the difference between the resulting
signals from two tissue regions. The route by which the protons release the energy
they absorbed from the radio-frequency pulse, thus reducing the transverse magnetisation
and causing signal decay, is known as relaxation. In MRI two independent relaxation
processes occur simultaneously: spin-lattice or longitudinal relaxation characterised
by the time constant T
1, and spin-spin or transverse relaxation, characterised by the time constant
T2.
[0004] Often, when suitable
T1- or
T2-weighting sequences are used, the natural contrast between two tissues is enough
to produce a diagnostically-useful image. However, some conditions do not lead to
specific enough changes in the relaxation times of the affected tissue though and
then a contrast agent is used to locally change the relaxation times of the diseased
tissue, improving the image contrast.
[0005] Most contrast agents work by shortening the relaxation times of the water protons
in the targeted tissue. T
1 contrast agents are based on paramagnetic metal ion chelates which make the tissue
appear brighter on the
T1-weighted image (positive contrast).
T2 contrast agents are usually superparamagnetic iron oxide nanoparticles which create
dark spots on the
T2-weighted image (negative contrast). T
1 agents are the most widely used and the majority of these are based on chelates of
the gadolinium ion (Gd
3+).
[0006] To be an effective T
1 agent the lanthanide chelate must significantly increase the proton relaxation rates
in water. Lanthanide elements are most commonly found in the +3 oxidation state (Ln
+3), corresponding to the electronic configuration [Xe]6s
24f
n. Gadolinium (Gd)is the seventh element in the lanthanide series and has an electronic
configuration [Xe]4f
7. This means that Gd
3+ has seven unpaired electrons, making it highly paramagnetic i.e. Gd(III) ions have
large permanent magnetic moments (due to electron spin angular momentum), but in the
absence of an external magnetic field these are randomly oriented. Due to its large
size the Gd(III) and other lanthanides ions typically have a coordination number of
nine in its complexes. As a free ion lanthanides, and in particular gadolinium, are
very toxic for the tissues but it is generally considered safe when said ions are
administrated as a chelated compound.
[0007] The level of toxicity depends on the strength of the chelating agent, also known
as ligand, chelator or sequestering agent. Usually these ligands are organic compounds
which form two or more separate coordinate bonds with a single central metal ion,
in this case, the gadolinium ion, inactivating it thus reducing or eliminating its
toxic effect in the tissues.
[0008] Polyaminopolycarboxylic acid compounds are the ligand type of choice because they
form exceptionally stable complexes with the Gd(III) ion, which can be explained by
a number of reasons. These compounds can be linear (such as pentetic acid or diethylene
triamine pentaacetic acid also named as DTPA) or macrocyclic (such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid, DOTA). Complexes of macrocyclic ligands are much more kinetically inert and
thus, present an exceptionally high solution stability.
[0009] Several contrast agents comprising gadolinium as the lanthanide are marketed, Magnevist®
(Bayer Healthcare) with gadopentetate dimeglumine, Multihance® (Bracco) with gadobenate
dimeglumine, Omniscan® (GE Healthcare) with gadodiamide, Optimark® (Mallinckrodt Inc.)
with gadoversetamide and the macrocyclic chelates Dotarem® (Guerbet) with gadoteric
acid, Prohance® (Bracco) with gadoteridol and Gadovist® (Bayer Healthcare) with gadobutrol.
[0010] In the body, the complexes of chelates with lanthanide are in a situation of chemical
equilibrium, which may lead to a risk of undesired release of the lanthanide, and
more especially of gadolinium. Release of Gd
3+ from the complex is said to be responsible for the toxicity associated with gadolinium
complexes; this release appears to be a consequence of Zn
2+, Cu
2+, and Ca
2+ transmetallation
in vivo.
[0011] A person skilled in the art is thus led to seek technical solutions that limit this
risk in order to solve the complex problem of tolerance in the patient as safely as
possible. This problem is all the more difficult since the administration of contrast
agents is often repeated during diagnostic examinations and/or for the guiding and
monitoring of the efficacy of a therapeutic treatment.
[0013] EP0270483 discloses contrast agents based on gadolinium with addition of one or more free ligands,
such DOTA (1,4,7,10-tetraazacyclododecane-1,9,7,10-tetraacetic acid), EDTA (ethylenediaminetetraacetic
acid) or DTPA (diethylene triamine pentaacetic acid) and/or one or more weak metal
complexes (presenting relatively low stability constant, such as calcium, magnesium,
zinc and iron) or their mixtures to pharmaceutical agents based on metal complexes
result in contrast agents with improved in vivo tolerance. These contrast agents are
prepared by addition of a certain amount of the free ligand to the metal complex in
aqueous medium, which is further evaporated to dryness in vacuum. However, there is
always a difference in the amount of components in the calculated formulation and
in the obtained formulation due to the presence of a variable amount of water in the
ligand, which generates an error in the exact amount of ligand that is introduced
in the formulation. This variation in water content can be important for certain ligands,
such as for DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TRITA
(1,4,7,10-Tetraazacyclotridecane-1,4,7,10-tetraacetic acid), TETA (1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic
acid), HP_D03A (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-(2-hydroxypropyl)),
D03A-butrol (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-[2,3-dihydroxy-1-(hydroxymethyl)propyl])
and depends on the conditions of temperature and relative humidity during drying and
filling of said ligands. In powder form they can contain between 0% and more than
10% water and the water content can change afterwards during contact with the atmosphere.
This change will be greater when the relative humidity conditions during the weighing
and filling step of the formulation are different from those during drying and filling
of the ligand itself. When the relative humidity during weighing for the formulation
step is higher than during the drying and filling step, the weight of the powder will
have increased because of water uptake from the atmosphere thus causing an error in
the exact weight of the ligand and thus in the composition of the formulated contrast
agent.
[0014] US4647447 discloses complex salts from the anion of a complexing acid and one or more central
ions of an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and, optionally,
also formed from one or more physiologically biocompatible cations of an inorganic
and/or organic base or amino acid. Said complex salts may be also coupled as conjugates
with biomolecules known to concentrate in a specific organ to produce more efficient
contrast agents. The contrast agents herein disclosed are produced by suspension or
dissolution of said complex salts in an aqueous medium, with or without additives,
followed by sterilization. This document also discloses the production of contrast
agents without isolating the respective complex salts. In this case, to avoid the
presence of free toxically active metal ions, such as Ga
3+, the chelating step is done by using colour indicators such as xylenol orange by
control titrations. According to
US4647447, the contrast agents obtained show great stability in vitro and in vivo and are exceptionally
well tolerated physiologically. However, the reliability of this process depends largely
on the type of chelate and lanthanide. In the case of highly hygroscopic chelates
it is not possible to assure that the correct balance between both is present in the
body, in particular when other ions are present, such Ca
2+, Zn
+2 and Cu
2+ which are able to replace the lanthanide ion in some extent, in the complex and thus
releasing these to the body.
[0015] WO2010130814 discloses a process for preparing contrast agents in powder form based on a lanthanide
chelate, said powder including an excess of free chelate of 0.002% to 0.4% mol/mol
to address the problem of in vivo intolerance of lanthanide chelates related to the
presence of free lanthanide ions in the formulation to be administered. Said process
includes a step a) of mixing the chelate and the lanthanide wherein the free chelate
is in excess in relation to the amount of the lanthanide; b) measuring the amount
of free chelate and adjusting said amount to an excess of 0.002 to 0.4% mol/mol in
relation to the amount of the lanthanide; and c) precipitating the complexing solution
obtained with or without the adjustment step in an organic solvent, thus obtaining
a powder of chelate-lanthanide, wherein said powder contains an amount of free chelate
in excess in relation to the amount of the lanthanide. Finally, excipients and water
are added to produce an injectable contrast agent composition. Once again, it is not
possible to assure that the correct balance between chelate and lanthanide is present
in the final formulation to be administered in particular in what regards when linear
chelates are used mainly due to their fast dissociation kinetics. Moreover, another
disadvantage of this process is that several steps are performed and adjusting the
amount of chelate in excess, in powder form, is not an easy and reliable way to obtain
the intended amount due to hygroscopic properties of these compounds.
[0016] WO2009103744 discloses a process to produce a liquid formulation comprising a complex of a macrocyclic
chelate with a lanthanide, having an excess of free chelate of between 0.02-0.4% and
comprising the steps of a) preparing a liquid formulation of said macrocyclic chelate
with the lanthanide; b) measuring the amount of the macrocyclic chelate in the formulation;
c) adjusting the amount of macrocyclic chelate in order to obtain an excess of free
chelate between 0.02-0.4% in relation to the amount of free lanthanide and that there
is no free lanthanide present in the final formulation. However, all these steps increase
the risk of occurring errors and of introducing microbiological contaminants. Furthermore,
it also makes the process expensive and time consuming.
[0017] It is thus desirable to obtain an optimized process for producing a pharmaceutical
liquid formulation comprising a complex of macrocyclic ligand with a lanthanide, which
can be used as contrast agent for magnetic resonance imaging with good tolerance in
vivo. Furthermore, it is also desirable to simplify the method for producing contrast
agents formulations at an industrial scale.
SUMMARY OF THE INVENTION
[0018] It is an object of the present invention to provide a process for for preparing a
macrocyclic ligand that allows measuring the amounts of said ligand in a fast and
accurate way.
[0019] It is another object of the present invention to provide a process for producing
a pharmaceutical liquid formulation comprising a complex of macrocyclic ligand with
a lanthanide or a similar compound that allows obtaining safe contrast agents in a
simple, straightforward and reliable process.
[0020] This object is realised by providing a process for preparing a material comprising
a macrocyclic ligand as defined in claim 1.
[0021] It is also provided a process for producing a complex material of a macrocyclic ligand
with a lanthanide or a similar compound as defined in claim 4.
[0022] Another object of the present invention is to provide a pharmaceutical liquid formulation
that can be used as a contrast agent comprising a macrocyclic ligand material prepared
according to the present invention, as defined in claim 7.
[0023] Further advantages and embodiments of the present invention will become apparent
from the following description and the dependent claims.
DESCRIPTION OF THE INVENTION
[0024] The present invention relates to a process for preparing a macrocyclic ligand material
and to a process for producing a pharmaceutical liquid formulation comprising a complex
of macrocyclic ligand with a lanthanide or a similar compound wherein said ligand
is prepared according to the present invention, in a fast and reliable way, by controlling
the exact weight of the macrocyclic ligand in the final formulation and encompasses
the following steps:
- calculating the necessary amount of a material comprising a macrocyclic ligand for
a formulation batch;
- measuring the moisture content of said material in a sample of the batch;
- calculating the total amount of moisture present in said batch and
- calculating the total amount of material which is required for preparing the batch
size.
[0025] The pharmaceutical liquid formulation is then produced by adding the remaining components
of the formulation, such as a lanthanide or a similar compound and excipients such
as meglumine, to the material comprising the macrocyclic ligand.
[0026] In one embodiment, the total amount of the material comprising a macrocyclic ligand
can be divided into a plurality of portions and distributed into unit packages under
controlled conditions of humidity.
[0027] In another embodiment, when a certain amount (Y) of material comprising a macrocyclic
ligand is taken as a sample for controlling purposes, ex. quality control, then said
amount (Y) may be added to the calculated amount of material in order to compensate
the amount that was taken for testing.
[0028] In the scope of the present invention the ligand is preferably a derivative of tetraaza
macrocycles such as 1,4,7,10-tetraazacyclododecane (cyclen), 1,4,7,10-tetrazacyclotridecan
(homocyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam), preferably DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid), NOTA (1H-1,4,7-Triazonine-1,4,7-triacetic acid, hexahydro), DOTAGA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic
acid, α-(2-carboxyethyl)), D03A (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid),
D03A-butrol (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]),
HP-D03A (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-(2-hydroxypropyl))
and PCTA (3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic
acid), more preferably DOTA, D03A, HP-D03A and even more preferably DOTA.
[0029] In the scope of the present invention, "lanthanides" comprise the fifteen metallic
chemical elements with atomic numbers 57 through 71, from lanthanum through lutetium.
"Similar compounds" comprise scandium and yttrium. Together with scandium and yttrium,
the trivial name "rare earths" is sometimes used to describe all the lanthanides and
similar compunds.
[0030] Preferred lanthanides and similar are Gadolinium (Gd), Yttrium (Y) and Terbium (Tb)
and most preferred is Gadolinium.
Description of a preferred embodiment of the invention
I - Process for preparing the macrocyclic ligand
[0031] In a first step it is necessary to calculate the necessary amount of material comprising
a macrocyclic ligand for producing a batch of a certain size to obtain the desired
contrast agent formulation. This material comprises active macrocyclic ligand which
may have moisture.
1. Calculating the necessary amount of macrocyclic ligand
[0032] The total amount of macrocyclic ligand (X1) for a specific batch must be calculated
in a way that it is present in the final formulation in an excess (Lf) in relation
of the total amount of lanthanide or a similar compound (G), being said amount (Lf)
in the range from 0.002% to 0.4% in relation of the amount of lanthanide or similar
compound, preferably in the range from 0.02% to 0.3%, more preferably in the range
from 0.025% to 0.25%, meaning that a small amount of excess ligand is added to the
formulation. This may ensure that metal traces originated during its production and/or
sterilization can be trapped, thus avoiding any possibility of replacement the lanthanide
or similar compound ions in the complex that may result in their release in free form
in the contrast agent formulation.
[0033] This means that in the final formulation there is an amount of macrocyclic ligand
forming a complex with lanthanide or similar compound (LG) and an amount in free form
(Lf), not complexing the lanthanide or similar compound ions and thus:

[0034] Wherein:
. X1 is the total amount of macrocyclic ligand present in the final contrast agent
formulation, i.e. the target amount of ligand able to form a complex;
. LG is the amount of macrocyclic ligand forming a complex with the lanthanide or
similar compound present in the final contrast agent formulation; and
. Lf is the amount of macrocyclic ligand in its free form present in the final contrast
agent formulation, which according to the present invention is in the range set out
above in relation of the total amount of the lanthanide or similar compound(G),
[0035] The size of the batch can be small, suitable for laboratory scale i.e. for example
of 250g, 500g 1000g, etc. or bigger sizes such as 20kg, 50kg, 200kg, 500kg, etc. for
pilot and industrial scale.
[0036] The total amount of macrocyclic ligand (X1) can be produced by any known method in
the art and is homogenised in a container. Said container may be the container where
the reaction for producing the ligand occurred, a blender, a homogeniser or any container
suitable for homogenising the obtained macrocyclic ligand in the desired amount for
a certain batch of formulation.
2. Measuring the moisture content of the material comprising a macrocyclic ligand
[0037] In this step, a sample of the homogenised material comprising the macrocyclic ligand
to be used in the batch in question is taken for analysis from the container in order
to determine the moisture content (M) of said batch. Based on this result, it is possible
to calculate the actual amount in weight of ligand with moisture (X3). Thus,

wherein,
- X3 is the target weight of material comprising the macrocyclic ligand + moisture for
the final formulation batch;
- X1 is the target weight of macrocyclic ligand excluding the moisture weight; and
- M is the weight of the moisture present in the material for the final formulation
batch.
[0038] Now it is possible to further calculate the amount of material comprising the macrocyclic
ligand necessary to fill each unit package when the batch is optionally divided into
portions. Thus,

[0039] Wherein,
X2 is the amount (X3) in weight of material comprising the macrocyclic ligand with
moisture (M) in each unit package; and (N1) is the number of unit packages for one
final formulation batch.
[0040] If the amount of material comprising the macrocyclic ligand + moisture is introduced
into the formulation, the amount of ligand available to form the complex with a lanthanide
or similar compound may be not enough when the amount of moisture (M) is not taken
into account. Therefore, by measuring M it is possible to know the exact amount of
ligand necessary to add to obtain a certain batch in order to avoid the presence of
free lanthanide.
[0041] In the embodiment where the material comprising a macrocyclic ligand is divided into
portions, each unit package is then filled with a homogenised and specifically measured
amount (X2) of material under controlled conditions of humidity so that the powder
ligand does not further absorb or desorb water during this phase. In consequence,
the real content of macrocyclic ligand able to form a complex with a lanthanide or
similar compound and of moisture in each unit package is known and thus no further
measurements or adjustments are needed; when it is desired to use a certain amount
of ligand to produce a batch of formulation it is only necessary to calculate the
number of unit packages to achieve the total amount of necessary ligand.
[0042] The total amount (X2) of the material of the batch can be divided into portions and
then packed. In such case, the amount (N1) of unit packages necessary to pack the
material comprising the macrocyclic ligand can be also calculated in function of the
total volume of the batch and the size of each unit package.
[0043] In another embodiment, the amount (X2) of material in each unit package takes into
account the removal of a certain quantity (Y) of said material for testing purposes,
ex. for quality control, certification purposes, etc. In this case, the amount (Y)
of material to be removed for testing must be calculated and added to the total amount
of material (X2) filled in each unit package to ensure that the total amount of macrocyclic
ligand calculated previously is maintained and available to form a complex.
[0044] Therefore, if a sample of, for example, 1g is needed to test the material comprising
the ligand for a determined purpose, such as certification, then the amount of material
(X2) in each unit package must be corrected by addition of 1g to X2 to result in the
exact amount of ligand necessary to produce a desired batch size, without the need
of further measurements or adjustments.
II - Process for producing a pharmaceutical liquid formulation
[0045] The remaining components necessary to obtain the liquid formulation comprising the
macrocyclic ligand, prepared as described above, are added to the material prepared
as described above or optionally to a certain number of unit packages in the desired
amounts in function of the different contrast agent formulations. Therefore, this
phase includes: a) the complex formation by addition of a selected lanthanide or similar
compound to the selected amount of material comprising a macrocyclic ligand, and b)
the addition of the necessary excipients to obtain a formulation with the desired
pharmaceutical properties. Examples of such excipients are water, meglumine, hydrochloric
acid and/or sodium hydroxide for pH adjustment.
3. Complex formation
[0046] The selected lanthanide or similar compound is added to the material comprising the
ligand to form the complex macrocyclic ligand with metal ion in the form of oxide
or salts thereof. The total amount of lanthanide or similar compound added to form
the said complex depends on the amount of ligand desired to form a complex (LG), i.e.
G should correspond to LG. The preferred lanthanide or similar compound is gadolinium,
terbium or yttrium, most preferable compound is gadolinium. The preferred form of
providing gadolinium is in the form of oxide, i.e. Gd
2O
3.
[0047] For this purpose, a mixture of material comprising the ligand and the lanthanide
or similar compound is dissolved in the exact desired amount in a reaction vessel.
No further measurements or adjustments are needed to produce a macrocyclic complex
with a lanthanide or similar compound.
[0048] The amount of lanthanide or similar compound (Gf) added must be calculated in order
to have no free lanthanide or similar compound in the final formulation, i.e. Gf =
0 in order to avoid toxicity problems associated with the administration of the contrast
agent in cause.
4. Adding the remaining components or excipients
[0049] The remaining excipients are added also to the reaction vessel containing the complex
of a macrocyclic ligand and the selected lanthanide or similar compound produced as
described above.
[0050] The macrocyclic ligand is present in the final liquid formulation in a concentration
in the range between 0.3 to 0.7 M, preferably in the range between 0.4 to 0.6 M and
most preferably at 0.5 M.
[0051] The intended amount of free ligand (Lf) in the liquid formulation is in the range
from 0.002% to 0.4 mol% in relation of the total amount of lanthanide or similar compound
(G), preferably is in the range from 0.02% to 0.3 mol%, more preferably in the range
from 0.025% to 0.25 mol% in relation to the total amount of lanthanide or similar
compound (G).
[0052] Examples of excipients added to the complex of a macrocyclic ligand with a lanthanide
or similar compound to obtain a liquid formulation as described above are water, an
organic base, hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is preferably
in a range from 4 to 8.5 and more preferably in a range from 6.5 to 7.9.
Measurements
[0053] The measurement of the content of water in DOTA is performed as described in the
semi micro method of Karl Fischer (Fischer, Karl - Pharm. Eur. 2.5.12)
EXAMPLES
[0054] All reagents used in the following examples were readily available from commercial
sources unless otherwise specified.
[0055] All reagents used to prepare DOTA and gadoterate meglumine, including 1,4,7,10-tetraazacyclododecane
(cyclen), Gd
2O
3 and N-methyl-D-glucamine, were obtained commercially and used as received.
Example 1 - Preparation of a 20 kg batch of macrocyclic ligand DOTA
[0056] This example illustrates the calculation for preparing an amount of macrocyclic ligand
for a batch size of liquid formulation of 200L. The selected ligand was DOTA and the
lanthanide or similar compound was Gadolinium. The concentration of gadoterate complex
in said formulation was 0.5M (M/L).
[0057] The total amount of DOTA (X1) was calculated in a way that it is present in the final
formulation in an excess (Lf) in relation of the total amount of lanthanide (G), being
said amount (Lf) in the range from 0.002% to 0.4% in relation of the amount of gadolinium,
preferably in the range from 0.02% to 0.3%, more preferably in the range from 0.025%
to 0.25%. A small amount of excess DOTA was then added to the formulation to accomplish
this target. This means that in the final formulation there was an amount of DOTA
forming a complex with gadolinium (LG) and an amount in free form (Lf), not complexed
with the gadolinium ions and thus:

Wherein
- X1 represents the total amount of DOTA present in the final contrast agent formulation;
- LG represents the amount of DOTA forming a complex with the gadolinium present in
the final contrast agent formulation; and
- Lf represents the amount of DOTA in its free form present in the final contrast agent
formulation, which according to the present invention is in the range set out above
in relation of the total amount of the gadolinium (G),
[0058] Therefore, for a batch of 200 L of liquid formulation at 0.5M:
X1 = 100.002 to 100.4 moles of DOTA; this corresponds to 40.443 to 40.603 kg of DOTA
100%;
LG = 100 moles of complexed DOTA with gadolinium;
Lf = 0.002 to 0.4 moles of free DOTA, to achieve 0.002% to 0.4% moles/moles in relation
of the amount of complexed gadolinium; assume a target Lf of 0.2% is calculated to
minimize the risk of obtaining a preparation that does not meet the requirements of
Lf between 0.002% and 0.4%. Therefore X1 should be 100.2 moles or 40.523 kg of DOTA;
G = 100 moles of complexed gadolinium; this corresponds to 50 moles of gadolinium
oxide (Gd2O3).
[0059] Assuming that the moisture content of the said batch of DOTA is 5.00%, the extra
weight of the moisture, M, is 2.026 kg and the total weight of DOTA + moisture, X2,
is 42.549 kg, to be divided in an integer number of unit packages N. If the number
of unit packages of N = 9 is chosen, then the weight of each unit package, X3, equals
4.728 kg.
Example 2 - Measuring the moisture content of the ligand
[0060] This and the next example illustrate how the moisture content in a batch of a macrocyclic
ligand changes when the product is exposed to different conditions of relative humidity.
[0061] The moisture content in the samples was measured using methods known to those skilled
in the art. In this example, the measurement of the content of water in DOTA was performed
as described in the semi micro method of Karl Fischer (Fischer, Karl - Pharm. Eur.
2.5.12).
[0062] Two samples of DOTA were kept in conditions of relative humidity (RH) = 30±5% at
a temperature of Temp = 20±2°C. From these samples, small samples ware taken at different
times (T0 = beginning of the experiment; T30 = T0 + 30 min; T90 = T0 + 90 min; and
T300 = T0 + 300 min) and the water content was measured as described above. Each experiment
(Exp.) was performed twice and the average of each (Ind.) was determined (Avg.). The
results in percentage of the initial weight of DOTA are shown in Table 1.
Table 1 - Determination of water content of DOTA at Temp. = 20±2°C and RH = 30±5%
|
Water content DOTA (%) |
|
Temp. = 20±2°C; RH = 30±5% |
|
T0 |
T30 |
T90 |
T300 |
|
Ind. |
Avg. |
Ind. |
Avg. |
Ind. |
Avg. |
Ind. |
Avg. |
Exp.1 |
4.941 |
4.94 |
4.944 |
4.98 |
5.038 |
5.00 |
5.178 |
5.15 |
|
4.929 |
5.020 |
4.954 |
5.114 |
Exp.2 |
5.346 |
5.25 |
6.154 |
6.20 |
6.062 |
6.12 |
6.106 |
6.19 |
|
5.150 |
6.247 |
6.170 |
6.268 |
[0063] These results show that at 30% RH the amount of moisture M in the batch increases,
thus increasing the weight of DOTA powder (X2).
Example 3 - Measuring the moisture content of the ligand in conditions of higher RH
[0064] This example, as the previous one, illustrates how the moisture content in a batch
of a macrocyclic ligand is affected by the environmental relative humidity conditions.
Therefore, the experiments of Example 2 were repeated in the same conditions but with
a RH = 75±5% instead of RH = 30±5% of Ex. 1. Again, each experiment (Exp.) was performed
twice and the average of each (Ind.) was determined (Avg.). The results in percentage
of the initial weight of DOTA are shown in Table 2.
Table 2 - Determination of water content of DOTA at Temp. = 20±2°C and RH= 75±5%
|
Water content DOTA (%) |
|
Temp.= 20±2°C; RH = 75±5% |
|
T0 |
T30 |
T90 |
T300 |
|
Ind. |
Avg. |
Ind. |
Avg. |
Ind. |
Avg. |
Ind. |
Avg. |
Exp.3 |
4.941 |
4.94 |
6.734 |
6.71 |
7.475 |
7.34 |
5.914 |
5.86 |
|
4.929 |
6.694 |
7.200 |
5.813 |
Exp.4 |
5.346 |
5.25 |
6.449 |
6.65 |
6.962 |
6.88 |
4.111 |
4.36 |
|
5.150 |
6.851 |
6.789 |
4.609 |
[0065] These results show that the water content in DOTA increases with the time and with
the relative humidity of the conditions and thus the high hygroscopicity of DOTA.
Example 4 - Preparation of a complex of DOTA with Gadolinium
[0066] In this example, the necessary amount of material comprising DOTA was divided into
portions and packed into several unit packages. Using the amounts mentioned in the
first Example, i.e. for a batch of liquid formulation of 200L, a Lf of 0.2% and for
a total amount of DOTA (X1) of 40.523 kg and a moisture content M of 5.00%, then the
total amount of DOTA + M (X2) equals 42.549 kg, to be divided in an integer number
of packages, e.g. 9 packages of 4.785 kg. This integer number of packages has to be
fed in the formulation reactor as such (no adjustment in the actual weight at the
time of filling the reactor is required).
[0067] The weight of gadolinium oxide for this batch should then be of 100 equivalents,
this is 50 moles or 18.125 kg of gadolinium oxide (Gd2O3) and thus, the meglumine
amount to be added is 100 moles, 19.521 kg.
1. A process for preparing a batch of a material which comprises a macrocyclic ligand
and may further comprise moisture, the process comprising the following steps:
- calculating the amount (X1) of a macrocyclic ligand which is necessary for the batch
size;
- measuring the amount of moisture which is present in one or more samples of said
batch;
- calculating the total amount (M) of moisture which is present in the batch; and
- calculating the total amount X3 = X1 + M of material which is required for preparing
the batch size.
2. A process according to claim 1 wherein an amount (Y) of material comprising the macrocyclic
ligand is added to the total amount X3 = X1 + M of material.
3. A process according to any of the claims 1 or 2 wherein the total amount (X3 = X1
+ M) of material comprising the macrocyclic ligand and moisture is divided into a
plurality of portions and packed into unit packages under controlled conditions of
humidity.
4. A process according to any of the claims 1 to 3 wherein the macrocyclic ligand is
DOTA, DO3A or HP-D03A.
5. A process, according to any of the claims 1 to 4 wherein the macrocyclic ligand is
DOTA.
6. A process for producing a complex of a macrocyclic ligand with a lanthanide or similar
compound, wherein a mixture of the material prepared according to any of the preceding
claims and a lanthanide or similar compound is dissolved thereby obtaining said complex
without a substantial amount of free lanthanide.
7. A process according to claim 6 wherein the lanthanide or similar compound is gadolinium,
terbium or yttrium.
8. A process according to claim 7 wherein the lanthanide or similar compound is gadolinium.
9. A process for producing a liquid formulation comprising a macrocyclic ligand and a
lanthanide or a similar compound, wherein:
- the complex of a macrocyclic ligand with a lanthanide or similar compound is prepared
according to any of the claims 6 to 8;
- the amount of said macrocyclic ligand in a free form is present in the final formulation
in an excess in the range from 0.02% to 0.4 mol% in relation to the total amount of
the lanthanide.
10. A process according to claim 9 wherein the amount of free macrocyclic ligand is present
in the final formulation in an excess in the range from 0.02% to 0.3 mol% in relation
to the total amount of the lanthanide or similar compound.
11. A process according to claim 10 wherein the amount of free macrocyclic ligand is present
in the final formulation in an excess in the range from 0.025% to 0.25 mol% in relation
to the total amount of the lanthanide or similar compound.
12. A process according to claim 9 wherein excipients are added to the formulation, said
excipients selected from water, an organic base, hydrochloric acid and/or sodium hydroxide
for pH adjustment.
13. A process according to claim 12 wherein the hydrochloric acid and/or sodium hydroxide
is added to obtain a pH in the range from 4 to 8.5.
14. A process according to claim 13 wherein the hydrochloric acid and/or sodium hydroxide
is added to obtain a pH in the range from 6.5 to 7.9.
15. A process according to claim 12 wherein the organic base is meglumine and/or a salt
thereof.
16. A process according to claim 9 wherein the lanthanide or similar compound is gadolinium,
terbium or yttrium and wherein the macrocyclic ligand is DOTA, DO3A or HP-DO3A and
the macrocyclic ligand is present in said liquid formulation in a concentration in
the range from 0.3 to 0.7 M.
17. A process according to claim 16 wherein the macrocyclic ligand is present in said
liquid formulation in a concentration in the range from 0.4 to 0.6 M.